Mucopolysaccharidosis IIIB (MPS IIIB, also known Sanfilippo Syndrome B, N-acetyl-α-D-glucosaminidase deficiency, and NAGLU deficiency) is a genetic, progressive, systematic, rare and devastating autosomal recessive lysosomal storage disease (LSD) caused by a deficiency in N-acetyl-α-D-glucosaminidase (i.e., N-acetyl-alpha-D-glucosaminidase abbreviated as NAGLU). NAGLU is a lysosomal enzyme required for the degradation of heparan sulfate as part of the stepwise breakdown of glycosaminoglycans (GAG) in the lysosome. In patients with MPS IIIB, genetic mutations result in a marked decrease in NAGLU enzyme activity, which leads to the accumulation of heparan sulfate (HS) in the brain and other organs. The accumulation of HS leads to progressive brain atrophy, neurocognitive decline, behavioral disturbances, speech loss, increasing loss of mobility, and premature death. With over almost 200 different mutations identified to date MPS IIIB exhibits extensive molecular and genetic heterogeneity.
Approximately 1 out of 200,000 births is affected by MPS IIIB, and the deficiency mainly manifests in young children. MPS IIIB typically presents during the first few years of life, and patients have a greater than 50 percent mortality rate by 17 years of age. After initial symptom-free interval, patients suffering from MPS IIIB usually present with a slowing of mental development and behavioral problems, followed by progressive intellectual decline resulting in severe mental retardation, dementia and motor disease. Acquisition of speech is slow and incomplete. Profoundly affected patients may present delayed psychomotor and speech development as early as 2 years of age. The disease usually progresses to increasing behavioral disturbance and sleep disturbance. Although the clinical features are mainly neurological, patients often develop diarrhea, carious teeth, an enlarged liver and spleen, stiff joints, hirsteness and/or coarse hair and may exhibit blood-clotting problems. In the final stage of the illness, patients become immobile and unresponsive and develop swallowing difficulties and seizure. The life-span of an affected child typically does not extend beyond late teens to early twenties.
There are no approved treatments for patients with MPS IIIB. Current supportive care is palliative for behavioral problems, sleep disturbances, seizures, and other complications, and does not address the root cause of MPS IIIB or stop disease progression. However, investigational enzyme replacement therapy utilizing a recombinant human NAGLU (rhNAGLU) is currently being investigated in clinical trials for patients with MPS IIIB. The enzyme is a recombinant form of the N-acetyl-α-D-glucosaminidase (NAGLU) enzyme intended to replace the missing or deficient NAGLU enzyme, with the goal of to reduce accumulated HS. See WO2013/055888, published Apr. 18, 2013; US Pat. Appl. Publication 2013/0095092 (Quinn et al.), published Apr. 18, 2013. A recombinant human NAGLU preferably omits all or a portion of the signal peptide (amino acids 1-13) that is present in naturally occurring human NAGLU (SEQ ID NO:1).